6.1 Dysfunction of the Intestinal Barrier
Histologically, the intestinal wall has four layers:
- (a)
mucosa,
- (b)
submucosa,
- (c)
muscular layer,
- (d)
serosa.
Mucosa with epithelial cells constitute a specific form of a “link with the outside world” and their role is to form a physical, chemical, and immune barrier. The epithelium, the most exposed part of the mucosa, is a glandular barrier with goblet cells that forms the luminal surface. Goblet cells secrete mucus, which lubricates the passage of food along and protects epithelium from digestive enzymes. In healthy individuals, the mucus layer protects the epithelium and the layers below from luminal bacteria and allows interactions mainly through the Peyer’s patches. Any diminished mucosal protection may lead to an increased bacterial adhesion and invasion, with a final inflammatory process. Disturbance in the mucosal barrier seems to be the key element in the onset of IBD and, subsequently, in the frequent relapses [7]. Alterations in the small vasculature of the mucosal layer, followed by the appearance of aphthous ulcers is the earliest pathological and endoscopic step in the course of IBD [8].
6.2 Immunological Reaction
The immune system plays a key role in the development of IBD. The implicated cells include intestinal epithelia, innate lymphoid cells, macrophages, dendritic cells, B cells, and T cells. The interaction of the antigen-presenting cells (APCs) with bacterial antigens leads to differentiation of naïve T-cells into effector T-helper cells, which occurs mainly in Peyer’s patches and lymphoid tissue. These reactions lead to immunological imbalance and overproduction of proinflammatory cytokines, especially interleukins and tumor necrosis factor-alpha.
Cytokines are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines can also be involved in autocrine signaling. The group of cytokines includes chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors, but generally no hormones or growth factors (despite some overlap in the terminology).
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells (leukocytes) [9]. The function of the immune system depends in large part on interleukins, and any irregularities in their turnover usually results in autoimmune diseases or immune deficiency.
Tumor necrosis factor alpha (TNF-α) is the best-known member of the cytokine subdivision called apoptosis cytokines. TNF-α is a monocyte-derived cytokine that has been implicated in tumor regression, septic shock, and cachexia [10, 11]. The protein is synthesized as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine [12].
In IBD, cytokine imbalance leads to a chronic intestinal inflammation. Clinical manifestations and inflammatory lesions in the intestinal wall are induced by elevated levels of several cytokines, mainly TNF-α. Recent studies point at other than TNF-α related pathways in the pathogenesis of IBD, in particular in CD, and suggest a strong link between IL-23, IL-17A, TNF-α and interferon γ (IFN-γ) [13, 14]. In a study by Hovhannisyan et al. [15], elevated levels of IL-17A were observed in the mucosa and serum of CD patients. This may suggest that in some cases IBD development may be due to an excessive activation of TNF-α pathway and simultaneous Th17 lymphocyte activation dependent on IL-23. Another study demonstrated that CD4+ Th17 lymphocytes are responsible for skin lesions and gut inflammation in IBD [16].
In case of CD the imbalance between proinflammatory and anti-inflammatory cytokines leads to a disproportionate activation of T helper (Th)1 cells and overproduction of interleukin (IL)-1β, IL-2, IL-10, IL-12, IL-18, transforming growth factor beta (TGF-β) and tumor necrosis factor-α (TNF-α) [13, 14]. The UC development seems to be Th2-dependent and the immune-mediated process leads to overproduction IL-4, IL-5, IL-6, IL-10, and IL-13 (Fig. 6.1).
Fig. 6.1
The abnormal activation of T helper (Th)1 and Th2 cells in the development of IBD
6.3 Risk Factors
6.3.1 Genetic Factors
The first proof for possible genetic basis in CD was provided by the studies on monozygotic twins and other familial clusters of IBD [17]. Lately, genome-wide association studies (GWAS) identified more than 150 genetic risk loci for IBD, 70 of which may be associated with CD. Recent, a great variation between European, American, and Asian populations was shown, with different gene mutations that can predispose to IBD, especially to CD [18].
The first CD GWAS was conducted in Japanese, in 2005, and identified tumor necrosis factor superfamily member 15 (TNFSF15) as a susceptibility locus (genetic variant, which increases the probability of contracting the disease but is not ‘necessary’ or ‘sufficient’ for disease expression) [17]. This was followed by a rush of studies from 2006 to 2008 [18–27], each including approximately 500–2000 CD cases and a similar number of controls genotyped at 100,000–600,000 single nucleotide polymorphisms (SNPs).
One of the most important associations in IBD pathogenesis is the polymorphism in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase recruitment domain-containing protein 15 (CARD15) gene. NOD2 is a protein in the NF-kB pathway and in humans it is encoded by the NOD2 gene located on chromosome 16 [28, 29]. NOD2 plays an important role in the immune system: it recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction, and acts as an intracellular sensor for bacterial wall components, especially muramyl dipeptide. Clinically, variants of NOD2 are associated with ileal involvement, a stenosing or fistulizing pattern of disease and a higher risk of surgery [30].
Other genetic variants that may lead to an increased risk of IBD are: toll-like receptor 4 (TLR-4), caspase recruitment domain-containing protein 9 (CARD9), interleukin 23 receptor (IL-23R), signal transducer and activator of transcription 3 (STAT3) for innate immunity, human leukocyte antigen, interferon regulatory factor 5 (IRF-5), protein tyrosine phosphatase non-receptor type 22 (PTPN-22) for adaptive immune system, etc. [18].
Recently, genetic variations in the autophagic pathway were shown to be the risk factors in IBD pathogenesis. Autophagy is a lysosomal recycling mechanism of the cytoplasm that plays an important role in the innate immune response toward intracellular bacteria. Yet another pathway with close interaction to the autophagic pathway is the unfolded protein response induced by endoplasmic reticulum stress. Autophagy-related 16-like 1 gene (ATG16L1) and immunity-related guanosine triphosphatase gene (IRGM) have been linked to a higher susceptibility of CD [31].
Micro-RNAs (miRNAs) usually contain about 22 nucleotides. These are small non-coding RNA molecules found in plants, animals and some viruses, that function in RNA silencing and post-transcriptional regulation of gene expression [32, 33]. Over 5400 miRNAs have been identified so far, each carrying possible implications in autoimmune-mediated diseases [18]. In the context of IBD, correlations to the NOD-like receptors, TLRs and T-helper cells, especially Th17, were mentioned [34]. Because these are only observational studies, their therapeutic application is not entirely clear. The limitations of these molecules are represented by difficulty to target a specific organ and the associated systemic adverse reactions. However, miRNAs depending on the type of IBD could become a biomarker of disease in the near future [35].
6.3.2 Environmental Factors
Long-term observations evidenced different frequency of IBD depending on the geographical region. Most importantly, higher occurrence of IBD was observed in highly developed countries, what suggests—among others—that low exposure to pathogenic infections could disturb the mucosal immune balance, thus increasing the risk of IBD [36]. Previous or present smoking has been typically associated with a higher risk of CD [37]. Nicotine is related to an increased epithelial cell apoptosis, a higher intestinal permeability, and also to changes in the mucosal immune response without a clearly proven correlation. Tobacco smoke constituents could also influence the intestinal immune balance by lowering T-cell proliferation and altering macrophagic response [38].
In the past smoking was noticed as protective factor of UC. In 2016, To et al. [39] conducted a meta-analysis about the effect of tobacco smoking on the natural history of UC. The study showed that smoking does not improve the natural history of UC. Given the health benefits of smoking cessation and the lack of clear benefit in UC, smoking cessation advice should thus be incorporated into guidance on the management of the disease.
Diet is considered a pathological trigger in some cases, as feeding habits can affect intestinal permeability and efficient clearance of bacterial antigens, consequently influencing the immune system [40]. In a recent study, Kawaguchi et al. [41] showed that food antigens can trigger CD4+ T cell activation in the mouse model of CD and are associated with high IgG plasma levels. With the help of GWAS correlated with nutrigenetic and nutrigenomic research, a new, more personalized approach to the patient with IBD is expected [41, 42]. There are clear evidences that nutritional therapy is highly successful in the treatment of CD. Exclusive enteral nutrition is well established as remission induction therapy. New diets, such as a CD exclusion diet or defined diets (specific carbohydrate diets, FODMAP diet, Paleolithic diet) are currently being discussed as treatment options for IBD patients [43].
6.3.3 Microbial Factors
6.3.3.1 Adherent-Invasive E. Coli
Interest in Escherichia coli as a pathogen in IBD began when it was shown that microorganisms isolated from patients with CD had greater adherent properties to human cells than those from controls, and that previously unrecognized invasive E. coli were present in Crohn’s ileal tissue [44–46].
Darfeuille-Michaud et al. [45] reported that E. coli was recovered from 65 % of chronic lesions in resected ileum and 100 % of biopsies of early lesions in postoperative endoscopic recurrence. Recent studies showed that E. coli strains are able to adhere to various human cells or cell lines. Wine et al. showed that 53–62 % of E. coli strains isolated from feces of CD were able to adhere to buccal cells, compared to only 5–6 % of those isolated from control subjects. In the same study, the correlation between bacterial adhesion to intestinal cells and intestinal colonization has been observed. The presence of high levels of bacteria creates a biofilm on the surface of the gut mucosa in patients with CD and UC [47, 48].
Glasser et al. [49] demonstrated that adherent-invasive Escherichia coli (AIEC) was able to survive and replicate in macrophages, without inducing host cells and stimulating the infected cells to release high levels of TNF-α.
6.3.3.2 Mycobacterium Avium Paratuberculosis
Mycobacterium avium subspecies paratuberculosis (MAP) is a pathogenic microorganism that causes Johne’s disease in ruminants and other animals such as primates and rabbits [50]. Because of clinical similarities between Johne’s disease in ruminants and IBD in humans, some researchers point at MAP as the cause of CD [44]. In line, similarly to CD MAP infection causes segmental and fibrosing stenosis, as well as epithelial granulomata [51]. Of note, in 1913 Dalziel et al. showed a correlation between CD and MAP [52]. Consequently, Naser et al. [53] cultured MAP from blood in up to 50 % of CD patients and 22 % of UC patients, but no control subjects. Curiously, antibiotic treatment against MAP does not cure IBD.
6.3.3.3 Helicobacter Pylori
Helicobacter pylori (HP) infection may be a protective factor against chronic inflammatory diseases, like IBD. A large study conducted by Väre et al. [54] confirmed the low prevalence of HP infection, especially in CD patients and showed that the age of onset of IBD was higher in seropositive than in seronegative patients.
In 2010, a meta-analysis that evaluated the possible relationship between IBD and HP infection was published. Luther et al. [55] showed that 27 % of the IBD patients had HP infection, in comparison to 40 % of the control group, with an estimated relative risk of infection of 0.64 %. The authors suggested a protective role of HP infection in IBD pathogenesis, but it was also noted that several heterogeneous factors could influence the study results [55].
In 2011, the same research group published a paper that tried to clarify the mechanism responsible for the inverse association of HP and IBD. The authors postulated that HP DNA in distal intestine could influence mucosal immunity. They also showed that it is capable of inhibiting the production of proinflammatory cytokines of the murine or human cells in vitro [56]. However, other studies have exposed that this lower prevalence of HP in IBD may be secondary to HP “spontaneous eradication” with 5-ASA or antibiotic treatment [57].
6.3.3.4 Clostridium Difficile
Clostridium difficile (C. difficile) is a gram positive bacillus and may become established in the human colon. C. difficile is present in 2–5 % of the adult population [58]. From time to time antibiotic therapy, especially clindamycin has the adverse effect of disrupting the normal balance of the gut flora, in which case C. difficile may opportunistically dominate, causing C. difficile colitis with watery diarrhea. Recent studies showed that in 40 % of the cases in IBD patients C. difficile colitis can appear without previous use of antibiotic [59, 60].
In 2013, Nitzan et al. [61] published an extensive review regarding the role of C. difficile in the pathogenesis of IBD, as well as its implications with respect to diagnosis and treatment. The review embraces different risk factors, clinical characteristics of the infection in IBD, special aspects of its presentation, diagnosis and treatment in IBD. It was noted that C. difficile infection in IBD patients most likely plays a role in the pathogenesis of exacerbations, although probably not in the development of IBD itself [61].
6.3.3.5 Viruses
Based on epidemiology studies, two theories about the relationship between viral infections and the development of IBD have been proposed. The first theory suggests that certain infections that occur during infancy may predispose to the appearance of IBD. The second theory, Hygiene Theory, points to the absence of infections in infancy and the lack of contact with certain antigens as the cause of subsequent intestinal inflammation. Several epidemiological studies about coincidence of viral infection and IBD development were conducted. Consequently, measles, mumps, cytomegalovirus, virus de Epstein-Barr were connected to IBD [62–66]. Nowadays rather implication in exacerbation, earlier age of IBD onset and viruses infections neither in IBD development is postulated.
Acknowledgments
Supported by the National Science Center (2015/17/N/NZ5/00677 to ASW).
References
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Mikhailov TA, Furner SE (2009) Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children. World J Gastroenterol 15(3):270–279CrossRefPubMedPubMedCentral
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